Arginine catabolism is essential to polymyxin dependence in Acinetobacter baumannii
Mei-Ling Han,
Yasser Alsaadi,
Jinxin Zhao,
Yan Zhu,
Jing Lu,
Xukai Jiang,
Wendong Ma,
Nitin A. Patil,
Rhys A. Dunstan,
Anton P. Le Brun,
Hasini Wickremasinghe,
Xiaohan Hu,
Yimin Wu,
Heidi H. Yu,
Jiping Wang,
Christopher K. Barlow,
Phillip J. Bergen,
Hsin-Hui Shen,
Trevor Lithgow,
Darren J. Creek,
Tony Velkov,
Jian Li
Affiliations
Mei-Ling Han
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia; Corresponding author
Yasser Alsaadi
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Jinxin Zhao
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Yan Zhu
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Jing Lu
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Xukai Jiang
National Glycoengineering Research Centre, Shandong University, Qingdao 266237, China
Wendong Ma
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Nitin A. Patil
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Rhys A. Dunstan
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Anton P. Le Brun
Australian Centre for Neutron Scattering, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, NSW 2232, Australia
Hasini Wickremasinghe
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Xiaohan Hu
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Yimin Wu
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Heidi H. Yu
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Jiping Wang
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Christopher K. Barlow
Monash Proteomics and Metabolomics Facility, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Phillip J. Bergen
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Hsin-Hui Shen
Department of Materials Science and Engineering, Faculty of Engineering, Monash University, Clayton, VIC 3800, Australia
Trevor Lithgow
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia
Darren J. Creek
Monash Proteomics and Metabolomics Facility, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
Tony Velkov
Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia
Jian Li
Infection Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre to Impact AMR, Monash University, Clayton, VIC 3800, Australia; Corresponding author
Summary: Polymyxins are often the only effective antibiotics against the “Critical” pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures. Here, we report that arginine metabolism is essential for polymyxin-dependent A. baumannii. Specifically, the arginine degradation pathway was significantly altered in polymyxin-dependent strains compared to wild-type strains, with critical metabolites (e.g., L-arginine and L-glutamate) severely depleted and expression of the astABCDE operon significantly increased. Supplementation of arginine increased bacterial metabolic activity and suppressed polymyxin dependence. Deletion of astA, the first gene in the arginine degradation pathway, decreased phosphatidylglycerol and increased phosphatidylethanolamine levels in the outer membrane, thereby reducing the interaction with polymyxins. This study elucidates the molecular mechanism by which arginine metabolism impacts polymyxin dependence in A. baumannii, underscoring its critical role in improving diagnosis and treatment of life-threatening infections caused by “undetectable” polymyxin-dependent A. baumannii.
